Over the past several decades, the frequency of antimicrobial resistance and its association with serious infectious diseases have increased at alarming rates. The increasing prevalence of pathogens resistant to one or more of the approved antibiotics for treating agents causing nosocomial infections, also called hospital-acquired infections, is particularly disconcerting. Of the over 2 million nosocomial infections occurring each year in the United States, 50 to 60% are caused by antimicrobial-resistant strains of bacteria. The high rate of resistance to commonly-used antibacterial agents increases the morbidity, mortality, and costs associated with nosocomial infections. In the United States, nosocomial infections are thought to contribute to or cause more than 77,000 deaths per year and cost approximately $5 to $10 billion annually. Only a few classes of approved antibacterials are effective on Gram-negative bacteria. Important causes of Gram-negative resistance include extended-spectrum β-lactamases (ESBLs) in Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis, high-level third-generation cephalosporin (Amp C) β-lactamase resistance among Enterobacter species and Citrobacter freundii, and multidrug-resistance genes observed in Pseudomonas species, Acinetobacter species, and Stenotrophomonas species.
The problem of antibacterial resistance is compounded by the existence of bacterial strains resistant to multiple families of antibacterials. For example, Pseudomonas aeruginosa isolates resistant to fluoroquinolones are virtually all resistant to additional antibacterial medicines as well. Much of the antibacterial discovery effort in the pharmaceutical industry is aimed at the development of drugs effective against Gram-positive bacteria. However, there is also a need for new Gram-negative antibacterials, which are in general more resistant to a large number of antibacterials and chemotherapeutic agents than are Gram-positive bacteria. Such antibacterial compounds acting on lipopolysaccharide biosynthesis have been reported, including various hydroxamic acid compounds: see for example WO2004/062601, WO2010/032147, WO2011/073845, WO2012/120397, and WO2012/137094. One lipopolysaccharide biosynthesis enzyme, UDP-3-O—(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase (LpxC), has been reported as a validated target for antibacterials (Mdluli, et al., Antimicrobial Agents and Chemotherapy, 50(6), 2178-84 (2006). While inhibitors of LpxC have been described, there remains a need for new LpxC inhibitors. The current invention provides new antibacterial hydroxamic acid compounds that are believed to act by inhibition of LpxC and that avoid at least some of the prevalent mechanisms of resistance to known antibacterial agents.